Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia

Abstract

Purpose: To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Methods: Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 10⁷) or high (5 × 10⁸) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months).

Results: At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups (P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not (P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR (P < .0001). Toxicity was comparable in both dose groups.

Conclusion: In patients with advanced CLL, a 5 × 10⁸ dose of CART-19 may be more effective than 5 × 10⁷ CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.

Trial registration: ClinicalTrials.gov NCT02640209.

FIG 1.

Overall survival. (A) Evaluable patients (n = 32) receiving a high dose (n = 24; red line) or low dose (n = 14; blue line) of CART-19 cells were followed for overall survival. Tick marks represent censored patients (log-rank test P = .84). (B) Evaluable patients who attained a complete response (CR; blue line) or less than a CR (red line) were followed for overall survival. Tick marks represent censored patients (log-rank test P = .035).

FIG 2.

Progression-free survival (PFS). (A) Patients receiving a high dose (blue line) or low dose (red line) of CART-19 cells were followed for PFS. Patients’ disease was scored as progressing if there was no response at the first evaluation time point (log-rank test, P = .19). (B) Patients whose disease attained a complete response (CR; blue line) or less than a CR (red line) were followed for PFS. Log-rank test P < .0001. (C) Patients with responding disease were divided into complete responders (blue) or partial responders (red). Log-rank test P = .0013.

FIG 3.

Association of cytokine release syndrome (CRS) with complete response (CR). The number of patients whose disease attained or did not attain a CR was graphed according to development of CRS (Fisher exact two-sided P = .42).

FIG 4.

Expansion and persistence of CART-19 cells. CAR T cells were quantified by quantitative polymerase chain reaction (qPCR; top) or flow cytometry (bottom) and charted for patients whose disease achieved a complete response (CR), partial response (PR), or no response (NR). Within each panel, data of patients who received the high dose of CART-19 cells are indicated in blue, and data of those receiving the low dose of CART-19 cells are in red. PB, peripheral blood.

FIG A1.

CONSORT diagram of all patients screened in the trial.

FIG A2.

Minimal residual disease (MRD) kinetics were charted over time in those patients with informative data sets who received the (A) low dose or (B) high dose of CART-19 cells and attained a complete response (CR; blue) or not (red). MRD was quantified using deep sequencing of IGVH (see Methods).

FIG A3.

Graphs of (A) overall survival (OS) and (B) progression-free survival (PFS) for all patients receiving low- or high-dose CART-19 cells, based on their assigned dose.

FIG A4.

Effect of minimal residual disease (MRD) on survival. Overall survival showed a trend toward improvement in patients with a deep remission at day 28 (defined as reduction in MRD > 3log₁₀).

FIG A5.

Association of selected cytokines with cytokine release syndrome (CRS) severity. Gr, grade.

FIG A6.

Durability of response by CART-19–cell expansion and persistence. (A) Patients with complete response. (B) Patients with relapsed disease after complete response.